PROJECT SUMMARY Two very recent advancements have been transforming the field of medical ultrasound. First, the revolutionary discovery of ultrasound neuromodulation, which non-invasively targets and modulates activity in specific regions of the brain. Second, contrast-enhanced super-resolution, which can image microvessels at resolutions as small as ten microns, an order of magnitude smaller than the ultrasound diffraction limit, and at greater depths. To achieve this generational leap in performance super-resolution contrast imaging requires that tens of thousands of frames of data be rapidly acquired and analyzed, making this technique much more computationally and algorithmically intensive than standard ultrasound imaging. Furthermore, the skull presents a unique challenge because it aberrates and generates reverberations, which reduce the resolution detectability of contrast agents. Consequently, transcranial super-resolution imaging would be difficult if not impossible to translate to the brain in its current form with current clinical hardware, especially if 3-D imaging is desired (which it is for functional imaging). Combining ultrasonic neuromodulation with functional imaging relies on MRI to target the ultrasound focus and to assess the brain?s functional response. However, confinement in a magnet bore, which typically requires anesthesia and limits the range observable behavioral scenarios. Furthermore, fMRI is slow compared to the time scale of the neural response, which is on the order of tens to hundreds of milliseconds. There is a solution to these limitations, which our group proposes to achieve in this project by developing a fully ultrasonic approach that combines 3-D super-resolution functional imaging with neuromodulation in a single integrated ultrasound platform that can be used on behaving animals. Time reversal, in conjunction with a highly accurate acoustic simulation tool that we have developed, can correct for the aberrations induced by the skull morphology accurately focus ultrasound and improve detectability. New software and implementation approaches designed at UNC Chapel Hill, including our innovative adaptive multi-focus beamforming approach, will simultaneously target multiple regions of the brain and enable full 3-D volume acquisitions at volume frame rates over 5000 FPS, suitable for rapid (hundreds of milliseconds) functional imaging. Recent advances in ultrasound hardware will enable ultra-high frame rate processing. Our research team at UNC Chapel Hill is partnering with a world- leading transducer group at NCSU to develop a lightweight wearable neurostimulation array. Ultra-fast processors, large RAM buffers, GPUs, and high-bandwidth data transfer hardware will be utilized to handle challenging adaptive beamforming tasks and massive data acquisition. Our approach will be validated in partnership with Vanderbilt, who have been pioneering the field of neuromodulation in non-human primates. Our motivation is to develop an integrated ultrasound platform as a new approach for neurostimulation and blood flow-based functional ultrasound imaging in the whole brain, with a non-ionizing, non-invasive, low-cost technology that could be used for monitoring and modulation in behaving animals.